Tissue eosinophils express the IL‐33 receptor ST2 and type 2 cytokines in patients with eosinophilic esophagitis

Uchida, Amiko M.; Lenehan, Patrick; Vimalathas, Praveen; Miller, Kaia C.; Valencia-Yang, Mabel; Li, Qiang; Canha, Lauren; Ali, Lestat; Dougan, Michael; Garber, John J.; Dougan, Stephanie K.

doi:10.1111/all.15127

Cited by 9 publications

(7 citation statements)

References 6 publications

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“…In addition to the role of TSLP, the IL-33/STR2 axis appears to be fundamental in the pathogenesis of EoE in humans [ 107 ]. Uchida et al reported frequent expression of the IL-33 receptor ST2 on esophageal-infiltrating eosinophils compared to blood eosinophils, other granulocytes, and Th2 cells.…”

Section: Resultsmentioning

confidence: 99%

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Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications

Rizzi

Presti

Chini

et al. 2023

JCM

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Food allergies are immuno-mediated adverse reactions to ingestion or contact with foods, representing a widespread health problem. The immune response can be IgE-mediated, non-IgE-mediated, or with a mixed mechanism. The role of innate immunity and alarmins in the pathogenesis of diseases such as asthma and atopic dermatitis is well known. Some authors have investigated the correlation between alarmins and food allergies, often obtaining interesting results. We analyzed articles published in English from the last 22 years present on PubMed concerning the role of alarmins in the pathogenesis of food allergies and their potential use as disease biomarkers, response biomarkers to therapy, or potential therapeutic targets. Nuclear alarmins (TSLP, IL-33, IL-25) appear to have a critical role in IgE-mediated allergies but are also implicated in entities such as eosinophilic esophagitis. Calprotectin and defensins may play a role as disease biomarkers and could help predict response to therapy, although results in the literature are often conflicting. Despite the promising results, more studies on humans still need to be conducted. Deepening our knowledge regarding alarmins and their involvement in food allergies could lead to the development of new biological therapies, significantly impacting patients’ quality of life.

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Section: Resultsmentioning

confidence: 99%

“…Eosinophils that lack antigen-specific T cell receptors maintained their ability to respond to IL33. This may explain the continued inflammation observed in patients with EoE after removal of dietary antigen [ 107 ].…”

Section: Resultsmentioning

confidence: 99%

Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications

Rizzi

Presti

Chini

et al. 2023

JCM

View full text Add to dashboard Cite

show abstract

“…Analysis of the EoE esophageal transcriptome has given rise a number of important hypotheses and guided critical follow-on mechanistic studies. Additional tools including immunohistochemistry, immunofluorescence, and flow cytometry have enabled assessment of tissue spatial distribution and expression levels of proteins and quantification and phenotyping of suspected culprit cells such as eosinophils, mast cells, basophils, T cells and group 2 innate lymphoid cells (ILC2s) comprising the immune microenvironment of the esophagus (16,24,25,(35)(36)(37)(38)(39). Immunohistochemistry and immunofluorescence have been used for many years to query spatial aspects and expression of various proteins, and electron microscopy of EoE esophagi revealed 80% of tissue eosinophils were in various stages of cytolysis (40).…”

Section: Human Esophageal Tissue Investigationsmentioning

confidence: 99%

Models and Tools for Investigating Eosinophilic Esophagitis at the Bench

Uchida

Garber

et al. 2022

Front. Immunol.

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Eosinophilic esophagitis (EoE) is an increasingly common food allergy disease of the esophagus that received its medical designation code in 2008. Despite this recency, great strides have been made in the understanding of EoE pathophysiology and type 2 immunity through basic and translational scientific investigations conducted at the bench. These advances have been critical to our understanding of disease mechanisms and generating new hypotheses, however, there currently is only one very recently approved FDA-approved therapy for EoE, leaving a great deal to be uncovered for patients with this disease. Here we review some of the innovative methods, models and tools that have contributed to the advances in EoE discovery and suggest future directions of investigation to expand upon this foundation.

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“…We recently showed that tissue resident eosinophils from patients with EoE have high expression of the IL-33 receptor, ST2 (3). IL-33 is a member of the IL-1 superfamily of inflammatory cytokines and has been shown to be important and elevated in allergic diseases such as EoE, asthma and atopic dermatitis (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Human differentiated eosinophils release IL-13 in response to IL-33 stimulation

Uchida

et al. 2022

Front. Immunol.

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ObjectiveEosinophils are hallmarks in allergic type 2 inflammation and are known to release cytotoxic granule proteins that contribute to inflammation. Eosinophils develop in the bone marrow from hematopoietic stem cells and once mature, have a limited lifespan in culture, making them difficult to study ex vivo. IL-33 has increasingly been shown as a key regulator of type 2 inflammation via signaling through its receptor, ST2. The present study was conducted to detail a method of eosinophil differentiation from hematopoietic stem cells and determine the response to IL-33.MethodsCD34+ and CD14+ cells were isolated from donor apheresis cones and differentiated into eosinophils or macrophage controls, respectively. Morphologic, transcriptional and protein analyses were performed to validate this method of eosinophil differentiation. The effect of IL-33 on differentiated eosinophils was assessed using qPCR, immunofluorescence, and multiplex cytokine array.ResultsCD34 differentiated eosinophils appear morphologically similar by H&E and express eosinophil peroxidase (EPX) protein as well as the conventional eosinophil transcripts EPX, CLC, and MBP. In addition, differentiated eosinophils expressed both isoforms of the IL-33 receptor, ST2L and sST2 throughout the differentiation process. Transcript levels of both IL-33 receptors were up-regulated by treatment with IL-33 at earlier timepoints in the differentiation. These cells also expressed IL-4 and IL-13 mRNA which were up-regulated by IL-33 as well. Notably, IL-13 expression was significantly higher with IL-33 treatment compared to media control at every timepoint measured. IL-33 significantly increased cellular secretion of IL-13 protein at most timepoints throughout differentiation. IL-8, LIF, CCL1, CCL5, CCL7, and CCL8 were also significantly secreted after IL-33 stimulation.ConclusionsOur findings suggest that CD34 differentiated eosinophils are morphologically and phenotypically similar to peripheral eosinophils. The release of specific cytokines in direct response to IL-33 may contribute to the pathogenesis of type 2 inflammation and facilitates new avenues for studying eosinophils as effector cells in vitro.

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Tissue eosinophils express the IL‐33 receptor ST2 and type 2 cytokines in patients with eosinophilic esophagitis

Cited by 9 publications

References 6 publications

Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications

Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications

Models and Tools for Investigating Eosinophilic Esophagitis at the Bench

Human differentiated eosinophils release IL-13 in response to IL-33 stimulation

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